Inhibiting Cell Cycle Progression and the Proteasome

The proteasome degrades ubiquitin-tagged proteins in the cytosol. Verma et al. (see the Perspective by Bellows and Tyers) performed a chemical genetic screen in Xenopus extracts to identify small-molecule inhibitors of cell-cycle progression. One class of inhibitors, the ubistatins, inhibited cyclin B degradation and thereby cell-cycle progression. Ubistatins also prevented the interaction of ubiquitinated substrates with purified proteasomes. Ubistatins target the same ubiquitin interface recognized by known, therapeutically important ubiquitin-binding proteins.